Gas body contrast agents bring a demonstrable risk of bioeffects to diagnostic ultrasound for the first time. Our research (and others throughout the world) has established the occurrence of micro-scale damage from contrast aided diagnostic ultrasound. Our laboratory has developed sensitive animal models and specific new tests for microscale bioeffects in heart and kidney. USFDA approved contrast agents and common diagnostic ultrasound scanners are used with carefully calibrated exposure methods to replicate not only the recommended doses and methods of administration of commercially available gas body contrast agents but also the attenuation and extended path lengths encountered in human exposures. It is therefore virtually certain that clinicians worldwide unknowingly cause similar microscale damage while obtaining diagnostic images with these methods. In our preliminary research on rat kidney, contrast gas bodies activated by diagnostic ultrasound ruptured the high pressure glomerular capillaries, and the resulting blood loss into the Bowman's capsule blocked entire nephrons and destroyed the resorptive epithelium of the proximal tubules. Our four specific aims will (1) examine the fundamental biophysics of the bioeffects at the microscopic level, (2) develop new dosimetric parameters and indices to aid clinicians in understanding and avoiding these bioeffects, (3) test common patient situations in which contrast ultrasound bioeffects potentially could result in medically significant injury, and (4) demonstrate ultrasound imaging methods which minimize bioeffects potential. Contrast aided diagnostic ultrasound appears to be a breakthrough for diagnosis but unfortunately progress has been stalled by the bioeffects problem, which is arguably the most pressing research need in medical ultrasound today. In this proposed research, experienced independent researchers will examine comprehensively this problem and resolve it. The establishment of principles and imaging procedures to insure safe use of contrast aided diagnostic ultrasound is urgently needed and achievable. Lay language: Contrast media have been invented to enhance ultrasound images by injecting small gas bubbles into the blood. After approval, research in animals has revealed microscopic damage in heart and kidney caused by the interaction of diagnostic ultrasound with the bubbles. This project will examine bioeffects in cells and tissues and show how to safely use ultrasound contrast agents in diagnostic imaging.